The C‐peptide fragment EVARQ reduces glomerular hyperfiltration in streptozotocin‐induced diabetic rats

Nordquist, Lina; Moe, Erika; Sjöquist, Mats

doi:10.1002/dmrr.704

Cited by 27 publications

(33 citation statements)

References 31 publications

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“…Our results from conscious rats confirm previous findings that the early onset of STZ-induced diabetes in rats results in glomerular hyperfiltration 16 , which is reversed by C-peptide administration 10 . These results clearly show that the applied method is suitable for detecting physiologically relevant changes in GFR in rats.…”

Section: Discussionsupporting

confidence: 92%

“…C-peptide is secreted from the islets of Langerhans together with insulin in equimolar amounts, and has been shown to influence physiological processes 7 . Several studies have also shown renoprotective effects of exogenous C-peptide administration to patients with type-1 diabetes 8,9 , but also to animals with experimental insulinopenic diabetes 9,10 . Such beneficial effects include decreased glomerular hyperfiltration, albuminuria, renal hypertrophy, and normalized glomerular volume 11 .…”

Section: Introductionmentioning

confidence: 98%

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C-Peptide Normalizes Glomerular Filtration Rate in Hyperfiltrating Conscious Diabetic Rats

Stridh

Sällström

Fridén

et al. 2009

Advances in Experimental Medicine and Biology

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Tubular electrolyte transport accounts for a major part of the oxygen consumed by the normal kidney. We have previously reported a close association between diabetes and increased oxygen usage, partly due to increased tubular electrolyte transport secondary to glomerular hyperfiltration during the early onset of diabetes. Several studies have shown that acute administration of C-peptide to diabetic rats with glomerular hyperfiltration results in normalized glomerular filtration rate (GFR). In this study, we validated a novel method for precise and repetitive GFR measurements in conscious rats and used C-peptide injection in diabetic rats for evaluation. First, GFR was determined in normoglycemic control rats before and after C-peptide administration. Thereafter, all rats were made diabetic by an i.v. streptozotocin injection. Fourteen days later, GFR was again determined before and after C-peptide administration. GFR was estimated from plasma clearance curves using a single bolus injection of FITC-inulin, followed by serial blood sampling over 155 min. FITC-inulin clearance was calculated using non-compartmental pharmacokinetic data analysis. Baseline GFR in normoglycemic controls was 2.10 +/- 0.18 ml/min, and was unaffected by C-peptide (2.23 +/- 0.14 ml/min). Diabetic rats had elevated GFR (3.06 +/- .034 ml/min), which was normalized by C-peptide (2.35 +/- 0.30 ml/min). In conclusion, the used method for estimation of GFR in conscious animals result in values that are in good agreement with those obtained from traditional GFR measurements on anaesthetized rats. However, multiple measurements from the same conscious subject can be obtained using this method. Furthermore, as previously shown on anaesthetized rats, C-peptide also normalizes GFR in hyperfiltrating conscious diabetic rats.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 98%

C-Peptide Normalizes Glomerular Filtration Rate in Hyperfiltrating Conscious Diabetic Rats

Stridh

Sällström

Fridén

et al. 2009

Advances in Experimental Medicine and Biology

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“…Infusion of C-peptide over 2 wk in STZinduced diabetic rats in the absence of insulin also prevents glomerular hyperfiltration as well as glomerular hypertrophy and microlabuminuria (87). Similar beneficial effects following treatment with several different doses of either full-length C-peptide or with its active COOH-terminal fragment EVARQ were observed in other studies using STZ-induced diabetic rats (43,74,88,99). Effects of C-peptide have also been studied in humans during early stages of diabetic nephropathy.…”

Section: Effects Of C-peptide In the Diabetic Kidneysupporting

confidence: 54%

“…However, despite overall improvements in treatment, diabetic nephropathy remains associated with high morbidity and mortality, indicating the need for the development of novel treatments, and in recent years, C-peptide has started to emerge as a potential novel therapeutic treatment for type 1 diabetesassociated end-organ complications, including diabetic nephropathy (43,47,74,88,99). This part of the review will focus on describing the mechanisms by which C-peptide is thought to protect the diabetic kidney.…”

Section: Effects Of C-peptide In the Diabetic Kidneymentioning

confidence: 99%

Physiological effects and therapeutic potential of proinsulin C-peptide

Yosten

Maric‐Bilkan

Luppi

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Connecting Peptide, or C-peptide, is a product of the insulin prohormone, and is released with and in amounts equimolar to those of insulin. While it was once thought that C-peptide was biologically inert and had little biological significance beyond its role in the proper folding of insulin, it is now known that C-peptide binds specifically to the cell membranes of a variety of tissues and initiates specific intracellular signaling cascades that are pertussis toxin sensitive. Although it is now clear that C-peptide is a biologically active molecule, controversy still remains as to the physiological significance of the peptide. Interestingly, C-peptide appears to reverse the deleterious effects of high glucose in some tissues, including the kidney, the peripheral nerves, and the vasculature. C-peptide is thus a potential therapeutic agent for the treatment of diabetes-associated long-term complications. This review addresses the possible physiologically relevant roles of C-peptide in both normal and disease states and discusses the effects of the peptide on sensory nerve, renal, and vascular function. Furthermore, we highlight the intracellular effects of the peptide and present novel strategies for the determination of the C-peptide receptor(s). Finally, a hypothesis is offered concerning the relationship between C-peptide and the development of microvascular complications of diabetes.

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“…Elegant studies by Nordquist et al [22] recently suggested a novel mechanism by which C-peptide may exert its beneficial effects on GFR. The protective effect, mediated by constriction of the afferent glomerular arteriole, net dilation of the efferent arteriole and inhibition of tubular Na + , reabsorption requires the C-terminal EVARQ fragment of C-peptide [23]. …”

Section: Role For C-peptide In Alleviating the Complications Of Diabementioning

confidence: 99%

C-Peptide as a Therapeutic Tool in Diabetic Nephropathy

2010

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Background/Aims: Insulin is synthesised as a pro-hormone with an interconnecting C-peptide, cleaved during post-translational modification. This review discusses growing evidence which indicates that C-peptide is biologically active, benefiting microvascular complications associated with diabetes. Methods: To explore the renoprotective role of C-peptide in diabetic nephropathy (DN), we reviewed the literature using PubMed for English language articles that contained key words related to C-peptide, kidney and DN. Results: Numerous studies have demonstrated that C-peptide ameliorates a number of the structural and functional renal disturbances associated with uncontrolled hyperglycaemia in human and animal models of type 1 diabetes mellitus that lead to the development and progression of nephropathy, including abrogation of glomerular hyperfiltration, reduced microalbuminuria, decreased mesangial expansion and increased endothelial nitric oxide synthase levels. The in vitro exposure of kidney proximal tubular cells to physiological concentrations of C-peptide activates extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, protein kinase C, elevates intracellular calcium, and stimulates transcription factors NF-ĸB and peroxisome proliferator-activated receptor-γ. Conclusion: Burgeoning studies suggest that C-peptide is more than merely a link between the A and B chains of the proinsulin molecule and represents a future therapeutic tool in reducing complications of DN.

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The C‐peptide fragment EVARQ reduces glomerular hyperfiltration in streptozotocin‐induced diabetic rats

Abstract: The present study shows that administration of the C-peptide fragment EVARQ has similar effects on GFR and blood glucose levels as the intact C-peptide molecule, suggesting at least one active site within this region.

Cited by 27 publications

References 31 publications

C-Peptide Normalizes Glomerular Filtration Rate in Hyperfiltrating Conscious Diabetic Rats

C-Peptide Normalizes Glomerular Filtration Rate in Hyperfiltrating Conscious Diabetic Rats

Physiological effects and therapeutic potential of proinsulin C-peptide

C-Peptide as a Therapeutic Tool in Diabetic Nephropathy

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